Top

Published in:

Open Access 01-12-2015 | Research article

First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy

Authors: Katrien Smets, Anna Duarri, Tine Deconinck, Berten Ceulemans, Bart P. van de Warrenburg, Stephan Züchner, Michael Anthony Gonzalez, Rebecca Schüle, Matthis Synofzik, Nathalie Van der Aa, Peter De Jonghe, Dineke S. Verbeek, Jonathan Baets

Published in: BMC Medical Genetics | Issue 1/2015

Abstract

Background

Identification of the first de novo mutation in potassium voltage-gated channel, shal-related subfamily, member 3 (KCND3) in a patient with complex early onset cerebellar ataxia in order to expand the genetic and phenotypic spectrum.

Methods

Whole exome sequencing in a cerebellar ataxia patient and subsequent immunocytochemistry, immunoblotting and patch clamp assays of the channel were performed.

Results

A de novo KCND3 mutation (c.877_885dupCGCGTCTTC; p.Arg293_Phe295dup) was found duplicating the RVF motif and thereby adding an extra positive charge to voltage-gated potassium 4.3 (Kv4.3) in the voltage-sensor domain causing a severe shift of the voltage-dependence gating to more depolarized voltages. The patient displayed a severe phenotype with early onset cerebellar ataxia complicated by intellectual disability, epilepsy, attention deficit hyperactivity disorder, strabismus, oral apraxia and joint hyperlaxity.

Conclusions

We identified a de novo KCND3 mutation causing the most marked change in Kv4.3’s channel properties reported so far, which correlated with a severe and unique spinocerebellar ataxia (SCA) type 19/22 disease phenotype.

Harding AE. Clinical features and classification of inherited ataxias. Adv Neurol. 1993;61:1–14.PubMed

Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9:885–94.CrossRefPubMed

Verbeek DS, Schelhaas JH, Ippel EF, Beemer FA, Pearson PL, Sinke RJ. Identification of a novel SCA locus (SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21-q21. Hum Genet. 2002;111:388–93.CrossRefPubMed

Duarri A, Jezierska J, Fokkens M, Meijer M, Schelhaas HJ, den Dunnen WF, et al. Mutations in potassium channel KCND3 cause spinocerebellar ataxia type 19. Ann Neurol. 2012;72:870–80.CrossRefPubMed

Lee YC, Durr A, Majczenko K, Huang YH, Liu YC, Lien CC, et al. Mutations in KCND3 cause spinocerebellar ataxia type 22. Ann Neurol. 2012;72:859–69.CrossRefPubMedPubMedCentral

Giudicessi JR, Ye D, Kritzberger CJ, Nesterenko VV, Tester DJ, Antzelevitch C, et al. Novel mutations in the KCND3-encoded Kv4.3 K+ channel associated with autopsy-negative sudden unexplained death. Hum Mutat. 2012;33:989–97.CrossRefPubMedPubMedCentral

Olesen MS, Refsgaard L, Holst AG, Larsen AP, Grubb S, Haunso S, et al. A novel KCND3 gain-of-function mutation associated with early-onset of persistent lone atrial fibrillation. Cardiovasc Res. 2013;98:488–95.CrossRefPubMed

Duarri A, Nibbeling E, Fokkens MR, Meijer M, Boddeke E, Lagrange E, et al. The L450P mutation in KCND3 brings spinocerebellar ataxia and Brugada syndrome closer together. Neurogenetics. 2013;14:257–8.CrossRefPubMed

Li-Smerin Y, Hackos DH, Swartz KJ. alpha-helical structural elements within the voltage-sensing domains of a K(+) channel. J Gen Physiol. 2000;115:33–50.CrossRefPubMedPubMedCentral

10.

Serodio P, Vega-Saenz De Miera E, Rudy B. Cloning of a novel component of A-type K+ channels operating at subthreshold potentials with unique expression in heart and brain. J Neurophysiol. 1996;75:2174–9.PubMed

11.

Tsaur ML, Chou CC, Shih YH, Wang HL. Cloning, expression and CNS distribution of Kv4.3, an A-type K+ channel alpha subunit. FEBS Lett. 1997;400:215–20.CrossRefPubMed

12.

Wang H, Yan Y, Liu Q, Huang Y, Shen Y, Chen L, et al. Structural basis for modulation of Kv4 K+ channels by auxiliary KChIP subunits. Nat Neurosci. 2007;10:32–9.CrossRefPubMed

13.

Gonzalez MA, Lebrigio RF, Van Booven D, Ulloa RH, Powell E, Speziani F, et al. GEnomes Management Application (GEM.app): a new software tool for large-scale collaborative genome analysis. Hum Mutat. 2013;34:842–6.CrossRefPubMedPubMedCentral

14.

Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012;366:636–46.CrossRefPubMed

15.

Schelhaas HJ, van de Warrenburg BP. Clinical, psychological, and genetic characteristics of spinocerebellar ataxia type 19 (SCA19). Cerebellum. 2005;4:51–4.CrossRefPubMed

16.

Dedek K, Kunath B, Kananura C, Reuner U, Jentsch TJ, Steinlein OK. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc Natl Acad Sci U S A. 2001;98:12272–7.CrossRefPubMedPubMedCentral

17.

Castaldo P, del Giudice EM, Coppola G, Pascotto A, Annunziato L, Taglialatela M. Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels. J Neurosci. 2002;22:RC199.PubMed

18.

Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, et al. A recurrent de novo mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet. 2015;47:39–46.CrossRefPubMed

19.

Orhan G, Bock M, Schepers D, Ilina EI, Reichel SN, Loffler H, et al. Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Ann Neurol. 2014;75:382–94.CrossRefPubMed

20.

Browne DL, Gancher ST, Nutt JG, Brunt ERP, Smith EA, Kramer P, et al. Episodic ataxia/myokimia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nat Genet. 1994;8:136–40.CrossRefPubMed

21.

Waters MF, Minassian NA, Stevanin G, Figuera KP, Bannister JP, Nolte D, et al. Mutations in voltage-gated potassium channel KCNC3 cause degeneratieve and developmental central nervous system phenotypes. Nat Genet. 2006;38:447–51.CrossRefPubMed

22.

Pena SD, Coimbra RL. Ataxia and myoclonic epilepsy due to a heterozygous new mutation in KCNA2: proposal for a new channelopathy. Clin Genet 2015. doi:10.1111/cge.12542.

23.

Skerritt MR, Campbell DL. Role of S4 positively charged residues in the regulation of Kv4.3 inactivation and recovery. Am J Physiol Cell Physiol. 2007;293:C906–14.CrossRefPubMed

24.

Skerritt MR, Campbell DL. Contribution of electrostatic and structural properties of Kv4.3 S4 arginine residues to the regulation of channel gating. Biochim Biophys Acta. 2009;1788:458–69.CrossRefPubMed

25.

Duarri A, Lin MC, Fokkens MR, Meijer M, Smeets CJ, Nibbeling EA, et al. Spinocerebellar ataxia type 19/22 mutations alter heterocomplex Kv4.3 channel function and gating in a dominant manner. Cell Mol Life Sci 2015, doi:10.1007/s00018-015-1894-1892.

26.

Wuttke TV, Jurkat-Rott K, Paulus W, Garncarek M, Lehmann-Horn F, Lerche H. Peripheral nerve hyperexcitability due to dominant-negative KCNQ2 mutations. Neurology. 2007;69:2045–53.CrossRefPubMed

27.

Hunter J, Maljevic S, Shankar A, Siegel A, Weissman B, Holt P, et al. Subthreshold changes of voltage-dependent activation of the K(V)7.2 channel in neonatal epilepsy. Neurobiol Dis. 2006;24:194–201.CrossRefPubMed

Title: First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy
Authors: Katrien Smets
Anna Duarri
Tine Deconinck
Berten Ceulemans
Bart P. van de Warrenburg
Stephan Züchner
Michael Anthony Gonzalez
Rebecca Schüle
Matthis Synofzik
Nathalie Van der Aa
Peter De Jonghe
Dineke S. Verbeek
Jonathan Baets
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: BMC Medical Genetics / Issue 1/2015
Electronic ISSN: 1471-2350
DOI: https://doi.org/10.1186/s12881-015-0200-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

First de novo KCND3 mutation causes severe Kv4.3 channel dysfunction leading to early onset cerebellar ataxia, intellectual disability, oral apraxia and epilepsy

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2015

Genes involved in muscle contractility and nutrient signaling pathways within celiac disease risk loci show differential mRNA expression

Functional characterisation of the osteoarthritis susceptibility locus at chromosome 6q14.1 marked by the polymorphism rs9350591

Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities

Hair shaft structures in EDAR induced ectodermal dysplasia

Physical activity, smoking, and genetic predisposition to obesity in people from Pakistan: the PROMIS study

Clinical characterization of int22h1/int22h2-mediated Xq28 duplication/deletion: new cases and literature review